Atypical Presentation of Gelsolin Amyloidosis in a Man of African Descent with a Novel Mutation in the Gelsolin Gene

Abstract

Patient: Male, 60Final Diagnosis: Atypical gelsolin amyloidosisSymptoms: Cranial nerve palsy • proximal muscle weaknessMedication: —Clinical Procedure: —Specialty: HematologyObjective:Rare diseaseBackground:Gelsolin amyloidosis is a very rare systemic disease presenting with a pathognomonic triad of corneal lattice dystrophy, cutis laxa, and polyneuropathy. The disease is mostly restricted to a Finnish population with known mutations (G654A, G654T) in exon 4 of the gelsolin gene. The mutations lead to errors in protein processing and folding, and ultimately leads to deposition of an amyloidogenic fragment in the extracellular space, causing the symptoms of disease.Case Report:We present a case of gelsolin amyloidosis in a male of African descent with an atypical clinical presentation including fevers, skin rash, polyneuropathy, and anemia. Gelsolin amyloidosis was diagnosed based on mass spectrometry of tissue samples. Importantly, a novel mutation in the gelsolin gene (C1375G) in exon 10 was found in this patient. His atypical presentation can possibly be attributed to the presence of a novel mutation in the gelsolin gene as the likely underlying cause of the syndrome. PCR primers were used to amplify the gelsolin gene from genomic DNA. Purified PCR products were then shipped to Eton Biosciences (San Diego, CA) for sequencing.Conclusions:This study carries several important lessons relevant to the practice of medicine. First, the differential diagnosis for multisystem disease presentations should always include amyloidosis. Second, despite what has been uncovered about the molecular biology of disease, there is always more that can be discovered. Finally, further work to verify the link between this mutation and the clinical syndrome is still needed, as are effective treatments for this disease.

Analyses Mutations in GSN, CST3, TTR, and ITM2B Genes in Chinese Patients With Alzheimer’s Disease

“…Followed by G194R and N211K mutations, whose clinical phenotype is different from D214N/Y, mainly gelsolin-related renal amyloidosis (Sethi et al, 2013;Efebera et al, 2014). A34fs, P459R, and A578P mutations were reported recently, corresponding totally different manifestations from mutations that we mentioned before (Feng et al, 2018;Oregel et al, 2018;Sridharan et al, 2018; Table 4). Patients with A34fs mutation presented with seizures and brain lesions, without skin and eye symptoms.…”

“…The GSN gene is located on the chromosome 9q33.2 and is inherited by dominance. Up to now, seven pathogenic mutations in the GSN gene have been reported in worldwide, namely A34fs, G194R, N211K, D214N, D214Y, P459R, and A578P (Figure 2 and Table 4, Hiltunen et al, 1991;Stewart et al, 2000;Conceição et al, 2003;Chastan et al, 2006;Ardalan et al, 2007;Huerva et al, 2007;Carrwik and Stenevi, 2009;Luttmann et al, 2010;Makioka et al, 2010;Asahina et al, 2011;Solari et al, 2011;Taira et al, 2012;Sethi et al, 2013;Efebera et al, 2014;Park et al, 2016;Caress et al, 2017;de Souza et al, 2017;Feng et al, 2018;Mustonen et al, 2018;Oregel et al, 2018;Sridharan et al, 2018). The D214N/Y mutation is the most common mutation and could cause the disease of FAF, which mainly manifested as corneal lattice dystrophy, cranial neuropathy, peripheral neuropathy, and cutis laxa (Nikoskinen et al, 2015).…”

Clinical and Histopathological Features of Gelsolin Amyloidosis Associated with a Novel GSN Variant p.Glu580Lys

“…These mutations increase the conformational flexibility of G2 and, as a consequence, the exposure of a stretch of the domain that is aberrantly cleaved by furin and matrix-metalloproteases with these proteolytic events leading to the production of amyloidogenic peptides [ 6 , 24 , 25 ]. Recently described mutations in G4 [ 16 , 17 ] and G5 domains [ 18 ], however, suggest an alternative and furin-independent pathway of gelsolin aggregation. The in silico model of the p.Glu580Lys variant predicts a net loss of connectivity and electrostatic repulsion caused by the Lys substitution, which might cause protein destabilization and misfolding, which are features often associated to pathological aggregation and aberrant proteolysis [ 26 ].…”

“…The mutation p.Glu580Lys described in the present study is also located in the G4:G5 interface and associated with the typical phenotype and supports the observation that mutations at various locations are able to produce classic phenotype of gelsolin amyloidosis and a common pathogenetic pathway. Reports of cases harboring other missense mutations in the domains G2 (p.Gly194Arg, p.Asn211Lys), G4 (p.Pro459Arg) and the G4:G5 interface (p.Ala578Pro) described more localized phenotypes including only renal, skin and/or heart disease without corneal lattice dystrophy [ 13 , 14 , 15 , 16 , 17 , 18 ]. These clinical presentations were still within the classic phenotypic spectrum and most reports included only a small number of cases, therefore, further studies are needed to conclude whether they cause identical or a limited/overlapping phenotype.…”

“…In recent years, cases harboring mutations of other residues of the GSN have also been reported. These substitutions reside in other domains of the protein and, in some cases, their clinical presentation diverge from the classical one [ 13 , 14 , 15 , 16 , 17 , 18 ]. Here we report clinical and histopathological features of gelsolin amyloidosis associated with a novel GSN variant c.1738G>A (p.Glu580Lys) and review phenotypes associated with all known GSN variants to date.…”